Marplan General Information

An MAO inhibitor that is effective in the treatment of major depression, dysthymic disorder, and atypical depression. It also is useful in the treatment of panic disorder and the phobic disorders. (From AMA, Drug Evaluations Annual, 1994, p311)

Medicinal name:

Marplan - Pharmacology:

Marplan works by irreversibly blocking the action of a chemical substance known as monoamine oxidase (MAO) in the nervous system. MAO subtypes A and B are involved in the metabolism of serotonin and catecholamine neurotransmitters such as epinephrine, norepinephrine, and dopamine. Marplan, as a nonselective MAO inhibitor, binds irreversibly to monoamine oxidase–A (MAO-A) and monoamine oxidase–B (MAO-B). The reduced MAO activity results in an increased concentration of these neurotransmitters in storage sites throughout the central nervous system (CNS) and sympathetic nervous system. This increased availability of one or more monoamines is the basis for the antidepressant activity of MAO inhibitors.

Marplan for patients

Patients should be instructed to report promptly the occurrence of headache or other unusual symptoms, i. e.,
palpitation and or tachycardia, a sense of constriction in the throat or chest, sweating, dizziness, neck stiffness,
nausea, or vomiting. Patients should be warned against eating the foods listed under CONTRAINDICATIONS while
on Marplan therapy and should also be told not to drink alcoholic beverages. The patient should also be warned about
the possibility of hypotension and faintness, as well as drowsiness sufficient to impair performance of potentially
hazardous tasks, such as driving a car or operating machinery.

Patients should also be cautioned not to take concomitant medications, whether prescription or over-the- counter
drugs such as cold, hay fever, or weight-reducing preparations, without the advice of a physician. They should be
advised not to consume excessive amounts of caffeine in any form. Likewise, they should inform their physicians and
their dentist about the use of Marplan.

Marplan Interactions

Marplan should be administered with caution to patients receiving Antabuse (disulfiram, Wyeth-Ayerst Laboratories). In a single study, rats given high intraperitoneal doses of an MAO inhibitor plus disulfiram experienced severe toxicity, including convulsions and death.

Concomitant use of Marplan and other psychotropic agents is generally not recommended because of possible potentiating effects. This is especially true in patients who may subject themselves to an overdosage of drugs. If combination therapy is needed, careful consideration should be given to the pharmacology of all agents to be used. The monoamine oxidase inhibitory effects of Marplan may persist for a substantial period after discontinuation of the drug, and this should be borne in mind when another drug is prescribed following Marplan. To avoid potentiation, the physician wishing to terminate treatment with Marplan and begin therapy with another agent should allow for an interval of 10 days.

Marplan Contraindications

Marplan (isocarboxazid) should not be administered in combination with any of the following: MAO inhibitors or
dibenzazepine derivatives; sympathomimetics (including amphetamines); some central nervous system depressants
(including narcotics and alcohol); antihypertensive, diuretic, antihistaminic, sedative or anesthetic drugs,
buproprion HCL, buspirone HCL, dextromethorphan, cheese or other foods with a high tyramine content; or excessive
quantities of caffeine.

Marplan (isocarboxazid) should not be administered to any patient with a confirmed or suspected cerebrovascular
defect or to any patient with cardiovascular disease, hypertension, or history of headache.

Contraindicated Patient Populations

Hypersensitivity

Marplan should not be used in patients with known hypersensitivity to isocarboxazid. Cerebrovascular Disorders
Marplan should not be administered to any patient with a confirmed or suspected cerebrovascular defect or to any
patient with cardiovascular disease or hypertension.

Pheochromocytoma

Marplan should not be used in the presence of pheochromocytoma, as such tumors secrete pressor substances whose
metabolism may be inhibited by Marplan.

Liver Disease

Marplan should not be used in patients with a history of liver disease, or in those with abnormal liver function
tests.

Renal Impairment

Marplan should not be used in patients with severe impairment of renal function. Patients with Severe/ Frequent
Headaches Patients with severe or frequent headaches should not be considered candidates for therapy with Marplan,
because headaches during therapy may be the first symptom of a hypertensive reaction to the drug.

Contraindicated MAOI-Other Drug Combinations

Other MAO inhibitors or with dibenzazepine-related entities Marplan should not be administered together with, or
in close proximity to, other MAO inhibitors or dibenzazepine-related entities. Hypertensive crises, severe convulsive
seizures, coma, or circulatory collapse may occur in patients receiving such combinations.

In patients being transferred to Marplan from another MAO inhibitor or from a dibenzazepine-related entity, a
medication-free interval of at least 1 week should be allowed, after which Marplan therapy should be started using
half the normal starting dosage for at least the first week of therapy. Similarly, at least 1 week should elapse
between the discontinuation of Marplan and initiation of another MAO inhibitor or dibenzazepine-related entity, or
the readministration of Marplan. The following list includes some other MAO inhibitors, dibenzazepine-related
entities, and tricyclic antidepressants.

Generic Name

Trademark
(Manufacturer)

Other MAO
Inhibitors

Furazolidone

Furoxone® (Roberts
Laboratories)

Pargyline HCL

Eutonyl® (Abbott
Laboratories)

Pargyline HCL and
methyclothiazide

Eutron® (Abbott
Laboratories)

Phenelzine sulfate

Nardil® (Parke-Davis)

Procarbazine

Matulane® (Roche
Laboratories)

Tranylcypromine sulfate

Parnate® (SmithKline Beecham
Pharmaceuticals)

Dibenzazepine- Related and Other
Tricyclics

Amitriptyline HCL

Elavil® (Zeneca)

Endep® (Roche
Products)

Perphenazine and amitriptyline
HCL

Etrafon® (Schering)

Triavil® (Merck Sharp &
Dohme)

Clomipramine
hydrochloride

Anafranil® (Novartis)

Desipramine HCL

Norpramin® (Hoechst Marion
Roussel)

Pertofrane® (Rhône-Poulenc Rorer
Pharmaceuticals)

Imipramine HCL

Janimine® (Abbott
Laboratories)

Tofranil® (Novartis)

Nortriptyline HCL

Aventyl® (Eli Lilly &
Co.)

Pamelor® (Novartis)

Protripyline HCL

Vivactil® (Merck Sharp &
Dohme)

Doxepin HCL

Adapin® (Fisons)

Sinequan® (Pfizer)

Carbamazepine

Tegretol® (Novartis)

Cyclobenzaprine HCL

Flexeril® (Merck Sharp &
Dohme)

Amoxapine

Asendin® (Lederle)

Maprotiline HCL

Ludiomil® (Novartis)

Trimipramine maleate

Surmontil® (Wyeth-Ayerst
Laboratories)

Bupropion

The concurrent administration of an MAO inhibitor and bupropion hydrochloride (Wellbutrin® and Zyban®,
Glaxo Wellcome) is contraindicated. At least 14 days should elapse between discontinuation of an MAO inhibitor and
initiation of treatment with bupropion hydrochloride.

Selective Serotonin Reuptake Inhibitors (SSRIs)

Marplan should not be administered in combination with any SSRI. There have been reports of serious, sometimes
fatal, reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations
of vital signs, and mental status changes that include extreme agitation and confusion progressing to delirium and
coma) in patients receiving fluoxetine (Prozac®, Lilly) in combination with a monoamine oxidase inhibitor (MAOI),
and in patients who have recently discontinued fluoxetine and are then started on an MAOI. Some cases presented with
features resembling neuroleptic malignant syndrome. Fluoxetine and other SSRIs should therefore not be used in
combination with Marplan, or within 14 days of discontinuing therapy with Marplan. As fluoxetine and its major
metabolite have very long elimination half-lives, at least 5 weeks should be allowed after stopping fluoxetine before
starting Marplan. At least 2 weeks should be allowed after stopping sertraline (Zoloft®, Pfizer) or paroxetine
(Paxil®, SmithKline Beecham Pharmaceuticals) before starting Marplan. In addition, there should be an interval of
at least 10 days between discontinuation of Marplan and initiation of fluoxetine or other SSRIs. Buspirone Marplan
should not be used in combination with buspirone HCL (Buspar®, Bristol-Myers Squibb); several cases of elevated
blood pressure have been reported in patients taking MAO inhibitors who were then given buspirone HCL. At least 10
days should elapse between the discontinuation of Marplan and the institution of buspirone HCL.

Sympathomimetics

Marplan should not be administered in combination with sympathomimetics, including amphetamines, or with
over-the-counter drugs such as cold, hay fever, or weight-reducing preparations that contain vasoconstrictors. During
Marplan therapy, it appears that some patients are particularly vulnerable to the effects of sympathomimetics when
the activity of metabolizing enzymes is inhibited. Use of sympathomimetics and compounds such as guanethidine,
methyldopa, methylphenidate, reserpine, epinephrine, norepinephrine, phenylalanine, dopamine, levodopa, tyrosine, and
tryptophan with Marplan may precipitate hypertension, headache, and related symptoms. The combination of MAO
inhibitors and tryptophan has been reported to cause behavioral and neurologic symptoms, including disorientation,
confusion, amnesia, delirium, agitation, hypomanic signs, ataxia, myoclonus, hyperreflexia, shivering, ocular
oscillations, and Babinski signs.

Meperidine

Meperidine should not be used concomitantly with MAO inhibitors or within 2 or 3 weeks following MAO therapy.
Serious reactions have been precipitated with concomitant use, including coma, severe hypertension or hypotension,
severe respiratory depression, convulsions, malignant hyperpyrexia, excitation, peripheral vascular collapse, and
death. It is thought that these reactions may be mediated by accumulation of 5-HT (serotonin) consequent to MAO
inhibition.

Dextromethorphan

Marplan should not be used in combination with dextromethorphan. The combination of MAO inhibitors and
dextromethorphan has been reported to cause brief episodes of psychosis or bizarre behavior.

Patients taking Marplan should not undergo elective surgery requiring general anesthesia. Also, they should not be
given cocaine or local anesthesia containing sympathomimetic vasoconstrictors. The possible combined hypotensive
effects of Marplan and spinal anesthesia should be kept in mind. Marplan should be discontinued at least 10 days
before elective surgery.

CNS Depressants

Marplan should not be used in combination with some central nervous system depressants, such as narcotics,
barbiturates, or alcohol.

Antihypertensives

Marplan should not be used in combination with antihypertensive agents, including thiazide diuretics. A marked
potentiating effect on these drugs has been reported, resulting in hypotension.

Caffeine

Excessive use of caffeine in any form should be avoided in patients receiving Marplan.